Abstract The progesterone receptor gene (PGR) is an estrogen receptor-? (ER) target gene. Thus, expression of progesterone receptors (PRs) in luminal breast cancers is a marker of active ER and predicts good response to endocrine therapy. However, recurrence of ER+ breast cancer occurs in ~40% of node-positive patients. Although breast cancer treatments that halt cancer cell proliferation, such as tamoxifen, are initially very effective, they fail to target slowly proliferating cells, including cancer stem and progenitor cell populations (CSCs) that contribute to recurrence. Resistance to endocrine-based therapies also develops over time. Clinical research supports a role for PR in endocrine failure, but the mechanisms are unknown. In fact, PRs have a profound impact on ER activity, although they are grossly understudied relative to ER. Two PR isoforms are equally expressed from the PGR gene in breast tissues: full-length PR-B and truncated PR-A. In normal tissues, PR isoforms most often function as A:B heterodimers. Imbalanced expression of PR isoforms typifies ER+ breast cancer, and thus reflects the presence of either A:A or B:B homodimers with overlapping and distinct functions. Both isoforms are also heavily modified by signaling pathways commonly elevated in breast cancer. In response to MAPKs or CDKs, PRs are phosphorylated on Ser294 (p-PRs) and enact gene programs associated with poor breast cancer outcome. ER+ breast tumors with PR isoform imbalance express abundant p-PRs, indicative of activated mitogenic signal transduction and aberrant SR function. This proposal addresses the hypothesis that p-PR modulates disease progression through ER-dependent and ER-independent functions. Together, these PR-driven events confer endocrine resistance, heighten insulin sensitivity, and increase breast cancer stem cells. We propose that p-PRs control these phenotypes through 2 primary mechanisms: 1) modulating ER function by regulating the adapter protein, insulin receptor substrate (IRS-1), increasing insulin sensitivity, resulting in endocrine resistance; and 2) evoking an oncogenic p- PR/FOXO1 signaling axis that is mediated by phosphorylated FOXO1 molecules. In this pro-signaling context, PRs can switch from inhibitors of ER function to activating ER partners at distinct target genes that drive advanced cancer phenotypes. PRs are thus under-exploited drivers of ER+ breast cancer progression. The proposed aims are 1) to determine how p-PRs alter global SR gene programs and to test the role of the insulin-receptor substrate-one (IRS-1) as a key ligand-independent p-PR-induced gene; 2) to determine how the p-PR/FOXO1 axis drives ER+ breast cancer; and 3) to determine the contribution of p-PRs to ER+ breast cancer progression in vivo using patient-derived xenograft models. There is an urgent need to delineate the actions of PRs as drivers of proliferation and cell fate transitions/plasticity that promote ER+ tumor progression. The discovery of targetable actions of PRs will help pave the way for development of durable combination endocrine therapies that block both ER and PRs, improving outcomes for patients with ER+ breast cancer.